Abstract
Administration of erucin (3 and 15 mg/kg) and sulforaphane (15 mg/kg) to rats for 10 days enhanced hepatic and pulmonary quinone reductase activity; sullforaphane also stimulated hepatic glutathione S-transferase, when monitored using 4-chloro-7-nitrobenzofurazan. Immunologically, both compounds increased the expression of hepatic and pulmonary glutathione S-transferases class a and p, but not n, proteins. Neither compound influenced activity of selected cytochromes P450, although CYP1A and CYP1B1 protein levels rose markedly in both tissues. The lack of concordance between activity and protein expression is due to the fact that isothiocyanates are mechanism-based inhibitors. A similar pattern of cytochrome P450 and Phase II enzyme modulation was observed when precision-cut rat liver and lung slices were incubated with either isothiocyanate. Both compounds elevated total glutathione, quinone reductase and glutathione S-transferase in rat liver and lung slices. In limited studies conducted with human slices, erucin and sulforaphane, in contrast to rat, were at best weak inducers of quinone reductase raising the possibility of species differences in the inducibility of this enzyme by isothiocyanates. Both isothiocyanates antagonised the benzo(a)pyrene-mediated induction of CYP1A in rat liver slices, and this may contribute to their chemopreventive activity. Urinary excretion of indirect-acting mutagens (unchanged 2-amino-3-methylimidazo-[4,5-f]quinoline) was significantly suppressed in rats pre-treated with isothiocyanates for 11 days prior to exposure to a single dose of 2-amino-3-methylimidazo-[4,5-f]quinoline, but hepatic CYPIA and glutathione S-transferase activities were unaffected, indicating that they are not responsible for the increase in the metabolism of this carcinogen. HPLC-MS methods were developed and validated for determining low sulforaphane levels in rat and human plasma. In rats, sulforaphane was rapidly absorbed, achieved high bioavailability but its pharmacokinetic behaviour was dose-dependent. Sulforaphane was also rapidly absorbed following intake of broccoli by human volunteers, achieving peak plasma levels within 1. 5 hours. Repeated intake of broccoli did not alter its pharmacokinetic behaviour.